John Isner, who at No. 11 is the top-ranked American man in the world rankings, said he will miss the French Open as he continues to recover from a left foot injury.
Isner, whose streak of 24 consecutive appearances at Grand Slam tournaments will come to an end, hurt the foot in the final of the Miami Open against Roger Federer at the end of March.
"Unfortunately, I have to withdraw from Roland Garros this year," Isner said in a Twitter post. "The foot injury I sustained in Miami has not fully healed and there's just no way I could possibly compete on the clay in Paris.
"While missing grand slams is not something I'm accustomed to, I've been fortunate to have such a clean bill of health my whole career. This is a bump in the road and I'm certain I will fully recover. Hope to see everyone at Wimbledon!"
Isner, 34, reached the fourth round of last year's French Open before falling to Juan Martin del Potro.
He was a Wimbledon semifinalist last year -- his best Grand Slam performance -- and hasn't missed a major since the 2013 Australian Open.
Isner is best known for winning the longest match in tennis history, 70-68 in the fifth set against Nicolas Mahut in Wimbledon's first round in 2010. The match lasted more than 11 hours over three days.
The Associated Press contributed to this report.